PROJECT SUMMARY Cardiovascular disease (CVD) is the primary cause of late mortality (death ?5 yrs from diagnosis) in early breast cancer (EBC). Effective treatment strategies that improve function across multiple systems are a major clinical need to reduce CVD in EBC. Aerobic exercise therapy (AT) is a pleiotropic intervention demonstrated in randomized controlled trials (RCTs) to improve cardiorespiratory fitness (CRF), a strong, independent predictor of CVD and all-cause mortality in BC and other malignancies. However, virtually all AT RCTs in oncology report the mean CRF change for the overall cohort; presentation of the mean result masks variability in responses. To directly address this gap, our group explored response variability in our recently completed RCT among 174 EBC patients (2.8 yrs. post-adjuvant therapy) who were allocated to 150 min/wk of: (1) linear AT (70% CRF); (2) nonlinear AT (55% to 100% CRF); or (3) stretching (attention control) for 16 consecutive wks. Despite high AT adherence, we found that: (1) CRF change ranged from -10% to +24%, and (2) ~60% were classified as CRF non-responders based on the CRF technical error (TE; a robust measure of biological variability and measurement error). These findings indicate that AT following the conventional volume (~150 min/wk) and / or length (~16 wks) is insufficient for improving CRF in a substantial proportion of EBC survivors. AT-induced improvement in CRF is associated with corresponding reductions in CVD risk; thus, there is a critical need to test the efficacy of alternative AT approaches that can optimize CRF response rate. Preliminary findings from our group, and others, indicate that in order to augment CRF, increased AT volume and / or length is required to allow for multisystem adaptation (i.e., across all components of the cardiopulmonary- vascular-muscular axis). There have been no RCTs directly assessing AT length and volume on CRF response rate in any cancer population. The objective of this study is therefore to evaluate the effects of AT program length and volume on CRF response rate and other pertinent outcomes in EBC. AIM 1: Compare the effects of nonlinear AT program length and volume on CRF response rates. AIM 2: Evaluate the effects on physiological determinants of CRF. AIM 3: Ascertain the difference in patient-reported outcomes, feasibility, and safety. Using a 4-arm RCT design, we will randomly allocate 152 (n=38/group) EBC survivors following completion of adjuvant therapy to: Arm A: volume only (300 min/wk for 16 weeks), Arm B: length only (150 min/wk for 32 weeks), Arm C: length and volume (300 min/wk for 32 weeks), or Arm D: control (150 min/wk for 16 weeks). IMPACT: Results from this investigation will identify the AT regimen that maximizes CRF response rate and other clinically relevant endpoints in EBC. Ultimately, these findings will inform policy, evidence-based guidelines, and standard clinical care.